Chelating carbene ligand precursors and their use in the synthesis of metathesis catalysts

ABSTRACT

Chelating ligand precursors for the preparation of olefin metathesis catalysts are disclosed. The resulting catalysts are air stable monomeric species capable of promoting various metathesis reactions efficiently, which can be recovered from the reaction mixture and reused. Internal olefin compounds, specifically beta-substituted styrenes, are used as ligand precursors. Compared to terminal olefin compounds such as unsubstituted styrenes, the beta-substituted styrenes are easier and less costly to prepare, and more stable since they are less prone to spontaneous polymerization. Methods of preparing chelating-carbene metathesis catalysts without the use of CuCl are disclosed. This eliminates the need for CuCl by replacing it with organic acids, mineral acids, mild oxidants or even water, resulting in high yields of Hoveyda-type metathesis catalysts. The invention provides an efficient method for preparing chelating-carbene metathesis catalysts by reacting a suitable ruthenium complex in high concentrations of the ligand precursors followed by crystallization from an organic solvent.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/295,773 filed Nov. 15, 2002, now U.S. Pat. No. 6,620,955, whichclaims the benefit of U.S. Provisional Application Ser. No. 60/334,781filed Nov. 15, 2001.

BACKGROUND OF THE INVENTION

Well-defined transition metal carbene complexes have emerged as thecatalysts of choice for a wide variety of selective olefin metathesistransformations [F. Z. Dörwald, Metal Carbenes in Organic Synthesis;Wiley VCH, Weinheim, 1999]. These transformations include olefin crossmetathesis (CM), ring-opening metathesis (ROM), ring-opening metathesispolymerization (ROMP), ring-closing metathesis (RCM), and acyclic dienemetathesis (ADMET) polymerization [K. J. Ivin and J. C. Mol, OlefinMetathesis and Metathesis Polymerization; Academic Press, London, 1997].Of particular importance has been the development of ruthenium carbenecatalysts demonstrating high activity combined with unprecedentedfunctional group tolerance [T. M. Trnka and R. H. Grubbs, Acc. Chem.Res., 2001, 34, 18–29]. Olefin metathesis serves as a key reaction forthe development of a range of regioselective and stereoselectiveprocesses. These processes are important steps in the chemical synthesisof complex organic compounds and polymers and are becoming increasinglyimportant in industrial applications. [see for example Pederson andGrubbs U.S. Pat. No. 6,215,019].

An initial concern about using ruthenium olefin metathesis catalysts incommercial applications has been reactivity and catalyst lifetime. Theoriginal breakthrough ruthenium catalysts were prinarily bisphosphinecomplexes of the general formula (PR₃)₂(X)₂Ru═CHR′ wherein X representsa halogen (e.g., Cl, Br, or I), R represents an alkyl, cycloalkyl, oraryl group (e.g., butyl, cyclohexyl, or phenyl), and R′ represents analkyl, alkenyl, or aryl group (e.g., methyl, CH═CMe₂, phenyl, etc.).Examples of these types of catalysts are described in U.S. Pat. Nos.5,312,940, 5,969,170 and 6,111,121. Though they enabled a considerablenumber of novel transformations to be accomplished, these bisphosphinecatalysts can exhibit lower activity than desired and, under certainconditions, can have limited lifetimes.

More recent developments of metathesis catalysts bearing a bulkyimidizolylidine ligand [Scholl et. al. Organic Letters 1999, 1, 953–956]such as 1,3-dimesitylimidazole-2-ylidenes (MES) and1,3-dimesityl-4,5-dihydroimidazol-2-ylidenes (IMES), in place of one ofthe phosphine ligands have led to greatly increased activity andstability. For example, unlike prior bisphosphine complexes, the variousimidizolyidine catalysts effect the efficient formation oftrisubstituted and tetrasubstituted olefins through catalyticmetathesis. Examples of these types of catalysts are described in PCTpublications WO 99/51344 and WO 00/71554. Further examples of thesynthesis and reactivity of some of these active ruthenium complexes arereported by A. Fürstner, L. Ackermann, B. Gabor, R. Goddard, C. W.Lehmarm, R. Mynott, F. Stelzer, and O. R. Theil, Chem. Eur. J., 2001, 7,No. 15, 3236–3253; S. B. Gaber, J. S. Kingsbury, B. L. Gray, and A. H.Hoveyda, J. Am. Chem. Soc., 2000, 122, 8168–8179; Blackwell H. E.,O'Leary D. J., Chatterjee A. K., Washenfelder R. A., Bussmann D. A.,Grubbs R. H. J. Am. Chem. Soc. 2000, 122, 58–71; Chatterjee, A. K.,Morgan J. P., Scholl M., Grubbs R. H. J. Am. Chem. Soc. 2000, 122,3783–3784; Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.;Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791–799; Harrity, J. P. A.;Visser, M. S.; Gleason, J. D.; Hoveyda, A. H. J. Am. Chem. Soc. 1997,119, 1488–1489; and Harrity, J. P. A.; La, D. S.; Cefalo, D. I; Visser,M. S.; Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 2343–2351.

The improvements in catalyst activity and expansion of potentialsubstrates resulted in the ruthenium metathesis systems becomingattractive candidates for use in industrial scale processes. Inparticular, many of the targeted products of olefin metathesis areuseful as intermediates in flavors and fragrances, pharmaceuticals andother fine chemicals. Thus, a second major concern has involvedruthenium residues that may be present in the products produced bymetathesis. To address this issue, several catalyst removal techniqueshave been developed [Maynard and Grubbs in Tetrahedron Letters 1999, 40,4137–4140; L. A. Paquette, JD. Schloss, I. Efremov, F. Fabris, F.Gallou, J. Mendez-Andino and J. Yang in Org. Letters 2000, 2,1259–1261;and Y. M. Ahn; K. Yang, and G. I. Georg in Org. Letters 2001, 3, 1411],including that described by Pederson and Grubbs [Pederson and Grubbs,U.S. Pat. No. 6,215,049] which is still the most amenable to large scalereactions. Ruthenium metathesis catalysts with a wide range ofreactivity and that could be easily removed from the product were nowavailable.

Further progress towards catalyst selectivity, stability, and removalhas been recently published by Hoveyda and others [Kingsbury, J. S.;Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H. J. Am. Chem. Soc.1999, 121, 791–799] with the demonstration of new, readily recyclablecatalyst systems containing chelating carbene species (FIG. 1) that areexceptionally stable and can even be purified by column chromatographyin air. For example, the tricyclohexylphosphine-ligated variant,Catalyst 601 (FIG. 1), can be recovered in high yield from the reactionmixture by simple filtration through silica. Hoyveda and coworkers alsodemonstrated [Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J. OrganometallicChemistry 2001, 624, 327–332] that by replacement of the phosphine withthe sMES ligand, Catalyst 627 (FIG. 1) actively promotes thecross-metathesis of acrylonitrile and terminal olefins in moderate toexcellent yields (20% to 91%) with a cis to trans olefin ratios thatrange from 2:1 to over 9:1. Related chelating carbene catalysts aredescribed in U.S. Patent Application Publication No. 2002/0107138 andU.S. Pat. No. 6,306,987.

FIG. 1

Prior methods used to make these chelating carbene complexes includetreating (Ph₃P)₃RuCl₂ with the appropriate diazo species at lowtemperature or treatment of a metathesis-active metal carbene complexwith the parent styrene in the presence of CuCl followed by columnchromatography (FIG. 2). While both of these methods yield the desiredcompound, they are difficult to scale up. Maintaining very lowtemperatures on larger reaction vessels requires expensive equipment,and diazo species are prone to violent decomposition under certainconditions. Using the o-isopropoxy styrene/CuCl route is also notamenable to large scale due to the requirement to purify the product bycolumn chromatography. A further shortcoming includes the use of theWittig reaction to yield the key styrene intermediate. Wittig reactionsare not convenient on a commercial scale because of the high costs ofthe reagents and the byproduct, triphenylphosphine oxide, produces anexcessive mass of waste. Alternatives to Wittig reactions would includeHeck, Stille or Suzuli coupling of vinyl trialkyltin, vinyl triflates orvinyl borate; respectively, to a halo-phenol substrate. These startingmaterials are generally expensive, and the reactions with trialkyl tinreagents involve toxic compounds which require special waste disposalprocedures. Finally the styrene itself is prone to polymerization undersome of the conditions required to make the “Hoveyda-type” catalysts.Therefore, there is a need for an efficient and economical synthesis tochelating carbene type ruthenium metathesis catalysts in largerquantities.

FIG. 2

The present invention describes efficient and versatile routes to usefuland valuable Hoveyda-type catalysts with chelating phenyl carbeneligands while eliminating expensive and toxic reagents. The presentinvention describes the synthesis of substituted olefins that areprecursors to catalyst complexes and their use as reagents to prepareolefin metathesis catalysts with chelating carbene ligands.

SUMMARY OF THE INVENTION

The present invention comprises methods for the use of novel chelatingligand precursors for the preparation of olefin metathesis catalysts.The resulting catalysts comprise monomeric species which are air stable,are capable of promoting various forms of metathesis reactions in ahighly efficient manner, and can be recovered from the reaction mixtureand reused.

One embodiment of the present invention is the use of internal olefincompounds, specifically beta-substituted styrenes, as ligand precursorsinstead of terminal olefin compounds such as unsubstituted styrenes FIG.3). Although internal olefins tend to be less reactive than terminalolefins, we have surprisingly found that the beta-substituted styrenesare sufficiently reactive to efficiently produce the desired catalystcomplexes. Compared with the styrene compounds, the beta-substitutedstyrenes are much easier and less costly to prepare in large quantitiesand are more stable in storage and use since they are less prone thanterminal styrenes to spontaneous polymerization.

FIG. 3

Another embodiment of the present invention are methods of preparingchelating-carbene metathesis catalysts without the use of CuCl aspreviously required. In previous reports, CuCl was used to sequesterphosphine ligands which shifts the equilibrium of metathesis reactionsto product formation. The use of CuCl in large scale synthesis isproblematic in that the resulting metathesis catalyst must be purifiedby chromatography before recrystallization, requiring large volumes ofsilica and solvent [Kingsbury et. al. J. Am. Chem. Soc. 1999, 121,791–799]. The present invention eliminates the need for CuCl byreplacing it with organic acids, mineral acids, mild-oxidants or evenwater, resulting in high yields of Hoveyda-type metathesis catalysts.The phosphine byproduct can be removed by an aqueous wash or filtration,thereby eliminating the chromatography step and allowing catalysts to bereadily isolated by crystallization from common organic solvents.

A further embodiment of the present invention is an efficient method forpreparing chelating-carbene metathesis catalysts by reacting a suitableruthenium complex in high concentrations of the novel ligand precursorsfollowed by crystallization from an organic solvent. For example, inthis manner Catalyst 601 can be simply isolated by filtering a hexanesolution of the reaction mixture resulting from the reaction of neatligand precursor and a ruthenium carbene complex. By using thebeta-substituted styrene derivatives, the excess, unreacted ligand isrecoverable from such reaction mixtures and can be reused. This isdifficult with the parent styrenes due to the propensity of thosematerials to polymerize under reaction and workup conditions.

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes the synthesis of “Hoveyda-type”chelating carbene metathesis catalysts from the cross metathesis ofnovel ligand precursors and metal carbene complexes. Although anymetathesis-active metal carbene complex is suitable for use in thepresent invention, preferred metal complexes include the Grubbs-typecompounds described in U.S. Pat. Nos. 5,312,940, 5,969,170, 6,077,805,6,111,121 and 6,426,419 and PCT publications WO 99/51344 and WO00/71554. These complexes have the general formulaX¹X²L¹(L²)_(m)M=CR¹R², wherein X¹ and X² are each, independently, anyanionic ligand; L¹ and L² are each, independently, any neutral electrondonor ligand; m is 1 or 2; M is ruthenium or osmium; and R¹ and R² areeach, independently, hydrogen or a group selected from the groupconsisting of alkyl, alkenyl, alkynyl, aryl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkoxycarbonyl, alkylthio, alkylsulfonyl,alkylsulfinyl and trialkylsilyl, any of which may be optionallysubstituted with a functional group selected from the group consistingof halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy,alkenyloxy, aryloxy, alkoxycarbonyl, carbonyl, alkylamino, alkylthio,alkylsulfonyl, nitrile, nitro, alkylsulfinyl, trihoalkyl,perfluoroalkyl, carboxylic acid, ketone, aldehyde, nitrate, cyano,isocyanate, hydroxyl, ester, ether, amine, imine, amide, sulfide,disulfide, sulfonate, carbanate, silane, siloxane, phosphine, phosphate,or borate. In these preferred metal carbene complexes, R¹ and R² may belinked to form a cyclic group, and any two or three of X¹, X², and L¹may be linked to form a multidentate ligand and two L² ligands, if m=2,may be linked to form a bidentate ligand. One type of chelating carbenecomplex, for example catalyst 601 or catalyst 627, may also be reactedwith the ligand precursors of the present invention to make differentchelating carbene complexes.

The ligand precursors of the present invention are fuctionalizedbeta-substituted styrene compounds, which may be conveniently preparedby the isomerization of functionalized allylbenzenes, with the structureshown in FIG. 4.

FIG. 4

Wherein:

-   -   Y is a heteroatom such as oxygen (O), sulfur (S), nitrogen (N),        or phosphorus (P);    -   Z is a group selected from hydrogen, alkyl, aryl, functionalized        alkyl, functionalized aryl where the functional group(s) may        independently be one or more or the following: alkoxy, aryloxy,        halogen, carboxylic acid, ketone, aldehyde, nitrate, cyano,        isocyanate, hydroxyl, ester, ether, amine, imine, amide,        sulfide, disulfide, carbamate, silane, siloxane, phosphine,        phosphate, or borate.    -   n is 1, in the case of a divalent heteroatom such as O or S, or        2, in the case of a trivalent heteroatom such as N or P;    -   R³ and R⁴ are independently selected from the group consisting        of hydrogen, C₁–C₂₀ alkyl, C₆–C₂₀ aryl, C₁–C₂₀ alkoxy or C₆–C₂₀        aryloxy;    -   R⁵, R⁶, R⁷, and R⁸ are each, independently, selected from the        group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl,        aryl, heteroaryl, alkoxy, alkenyloxy, aryloxy, alkoxycarbonyl,        carbonyl, alkylamino, alkylthio, alkylsulfonyl, nitrile, nitro,        alkylsulfinyl, trihaloalkyl, perfluoroalkyl, carboxylic acid,        ketone, aldehyde, nitrate, cyano, isocyanate, hydroxyl, ester,        ether, amine, imine, amide, sulfide, disulfide, sulfonate,        carbamate, silane, siloxane, phosphine, phosphate, or borate.        Additionally, any two or more of R⁵, R⁶, R⁷, and/or R⁸ may be        independently connected through hydrocarbon or functionalized        hydrocarbon groups forming aliphatic or aromatic rings.        Furthermore, one who is skilled in the art will recognize that        R⁸ should be chosen such that its steric bulk or chemical        functionality does not interfere with the cross-metathesis        reaction between the ligand precursor and the metal carbene        complex. Any one or more of R⁵, R⁶, R⁷ and R⁸ (but preferably        any of R⁵, R⁶ and R⁷) may be a linker to a solid support such as        silica, swellable polymeric resins, dendritic polymers, and the        like as, for example, described in U.S. Patent Application        Publication No. 2002/0107138 or by Grela (et al.) in Tetrahedron        Letters, 2002, 43, 9055–9059 for terminal-styrene ligand        precursors.

Preferred ligand precursors are beta-methyl styrenes wherein Y is oxygenor sulfur, n is 1; Z is alkyl, aryl or trialkylsilyl; and R³ and R⁴ areboth hydrogen. Particularly preferred ligand precursors arealkoxy-substituted beta-methyl styrenes wherein Y is oxygen; n is 1; Zis methyl, isopropyl, sec-butyl, t-butyl, neopentyl, benzyl, phenyl ortrimethylsilyl; and R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are all hydrogen. Examplesof particularly preferred ligand precursors of these types include2-methoxy-β-methylstyrene, 2-isopropoxy-β-methylstyrene and2-isopropoxy-3-phenyl-β-methylstyrene:

The precursor compounds for chelating ligands are easily prepared inhigh yields from commercially available starting materials. Treatment ofallyl aryl compounds with an isomerization catalyst cleanly migrates thedouble bond one carbon closer to the aryl ring forming abeta-substituted styrenic olefin (FIG. 4). We have found that(PPh₃)₃RuCl₂ is a preferred, highly active isomerization catalyst thatis effective at amounts ranging from about 0.001 to 20 mole percentrelative to the allyl aryl compound. It is preferable to isomerize theallylphenol compounds prior to further functionalization, since thehydroxy protons serve to activate the catalyst and the reactions cantherefore be run neat. For other compounds without their own proticsource, it is necessary to add an alcohol or other proton source toinitiate the isomerization catalysis. From the structures shown in FIG.4, one skilled in the art can appreciate the diversity of substitutionon the aromatic system that can be achieved. This allows the ligand tobe fine-tuned for specific applications. For the case where Y is oxygen,a wide variety of allyl phenol starting materials are easily produced bythe Claisen rearrangement (FIG. 5) of allylic aryl ethers [March'sAdvanced Organic Chemistry; 5^(th) Edition, Eds. M. B. Smith and J.March; John Wiley and Sons, New York, N.Y. 2001, pp. 1449–1452]. Similarrearrangements are operative for the case where Y is nitrogen, althoughmore forcing conditions are typically required.

FIG. 5

The above described ligand precursors can be used to prepare metathesiscatalysts with a chelating carbene group. The preferred chelatingcarbene complexes have the structure shown in FIG. 6. The most preferredchelating carbene complexes that are made by this method areHoveyda-type complexes including, but not limited to, catalyst 601 andcatalyst 627. In the most basic practice of the present invention, aswith the parent styrenes, it is possible to mix a metathesis activemetal carbene complex with the ligand precursor in a suitable solvent toeffect the transformation. Preferred solvents typically include, but arenot limited to, chlorinated solvents (such as methylene chloride,dichloroethane, chlorobenzene, and dichlorobenzenes), ethereal solvents(such as tetrahydrofaran or dioxane), aromatic solvents (such asbenzene, toluene, or xylenes), and hydrocarbon solvents (such ashexanes, heptane, and petroleum distillate fractions). In general, atleast one equivalent, and preferably an excess amount, of the ligandprecursor is utilized. Depending upon the reactivity of themetathesis-active metal carbene complex, the reaction may proceed atroom temperature, or even lower, or may need to be heated. As theprogress of these reactions can be conveniently monitored by a varietyof techniques including thin-layer chromatography (TLC), those skilledin the art can readily ascertain the appropriate conditions of time andtemperature to achieve high conversions to the desired chelating carbenecomplexes.

FIG. 6

In general, these reactions proceed more slowly and/or require somewhathigher reaction temperatures than comparable reactions with terminalstyrenes. In order to increase the reaction rates and achieve higherconversion, high ratios of ligand precursor to metal carbene complex canbe utilized. In fact, in the practice of the present invention, thereaction can be performed using neat ligand precursor as the solvent. Ingeneral, three to ten mole-equivalents of ligand precursor will givereasonable reaction rates and high conversions, although higher amountsmay be used. This approach cannot be utilized with the terminal styreneligand precursors due to their propensity to spontaneously polymerizeunder the reaction conditions. Upon completion of the reaction, theligand precursor can be distilled off of the reaction mixture and thechelating carbene product recrystallized from an appropriate solventAlternatively, the chelating carbene product can be precipitated by theaddition of an appropriate nonsolvent and the unreacted ligand precursorrecovered by distillation of the mother liquor. The beta-substitutedstyrene compounds are sufficiently robust so that high recoveries can beachieved by these methodologies, which would not be practical with theeasily polymerized terminal styrenes.

In general, treatment of one mass equivalent of a ruthenium carbenecomplex with between 1 and 20 mass eqivalents of ligand precursor in thepresence of an optional co-solvent (generally between about 1–20 massequivalents relative to the ruthenium complex) yields a thick mixturethat gradually looses viscosity during the course of the reaction.Optionally the mixture can be heated or cooled. The mixture may also beexposed to a static or dynamic vacuum. The reaction is preferablyconducted under an inert atmosphere but may be conducted in air unlessthe metal carbene complex is particularly air-sensitive. After 3 hoursto 7 days of string, the reaction is usually complete and the productmay be isolated as described above.

A complementary method for increasing reaction rates and conversionutilizes an additive to sequester the ligand that is displaced from themetal carbene complex during the course of the reaction. When thedisplaced ligand is a phosphine ligand, as is typical, the sequesteringagent that has been commonly used in cuprous cloride (CuCl), althoughthis is difficult to separate from the product without usingchromatograhy which is impractical at large scale. Suprisingly, we havefound that replacement of the CuCl with mineral acids, organic acids ormild oxidants in the presence of the ligand precursors of the presentinvention is also very effective. Treatment of ruthenium carbenecomplexes with between 1 to 10 equivalents of ligand precursor andbetween 0.1 to 10 equivalents acid or mild oxidant yields the newcatalyst containing the chelating carbene moity. After the reaction iscomplete, the displaced ligand and the sequestering agent can be readilyremoved from the mixture by extraction into water. The product can thenbe simply crystallized from the resulting solution in organic solventsin very high yield, eliminating the need for column chromatography.Preferred sequestering agents include hydrochloric acid, solutions ofhydrogen chloride in ethereal solvents (such as diethyl ether,tetrahydrofuran, or dioxane), gaseous hydrogen chloride dissolved in thereaction mixture, glacial acetic acid, bleach, and dissolved oxygen.Water can be utilized as a sequestering agent for particularly basicligands such as tricyclohexylphosphine (TCHP or PCy₃). The use ofsequestering agents is particularly perferred when using very robustmetal carbene complexes such as those containing IMES or sIMES ligands.When using less robust complexes such as ruthenium carbenes ligated withtwo phosphine ligands, greater care is needed and it is desirable toutilize the mildest sequestering agents or to slowly add thesequestering agents over the course of the reaction.

EXAMPLES Example 1

Synthesis of o-hydroxy beta-methyl styrene [1] from 2-allylphenol. To adry 100 mL round-bottom flask containing a magnetic stirbar was added 25g (186 mmol) of 2-allylphenol (Aldrich). The flask was sparged withargon for 30 minutes, followed by the addition of 71 mg (0.05 mol %) of(PPh₃)₂Cl₂Ru, a highly effective double-bond isomerization catalyst, andthen heated to 70° C. for 17.5 hours. GC analysis* indicated >99%conversion of 2-allyl phenol to o-hydroxy beta-methyl styrene. GCresults show ortho-hydroxy beta-methyl styrene R^(t) 8.51 minutes andR^(t) 11.13 minutes (Z and E Isomers), and 2-allylphenol R^(t) 8.86minutes. The catalyst was removed with tris-hydroxymethyl phosphine(THP), as previously described by Pederson and Grubbs [U.S. Pat. No.6,219,019], to yield 25 g, quantitative yield. Isomeric ratio of E:Zisomers was 45:55.

*GC Analysis: HP 5890 GC with DB 225 capillary GC column (30 m×0.25 mmID×0.25 um film thickness) Head pressure 15 psi, FID detection. Method:100° C. for 1 minute then 10° C./minute to 210° C. for 6 minutes.

Example 2

Synthesis of ortho-Isopropoxy beta-Methyl Styrene [2]. Protection of anaromatic hydroxyl group with isopropyl was as described by T. Sala andM. V. Sargent, J. Chem. Soc., Perkin Trans. 1, 2593, (1979). To a dry500 mL round-bottom flask containing a magnetic stirbar was added 50 g(373 mmol) of ortho-hydroxy beta-methyl styrene, 57.3 g (466 mmol)isopropyl bromide, 300 mL of anhydrous dimethylformamide (DMF), and 64 g(466 mmol) K₂CO₃. The heterogeneous mixture was warmed to 60° C. After 9hours the reaction was 57% converted, 30 g (244 mmol) isopropyl bromideand 32 g (232 mmol) of K₂CO₃ was added, and stirring was continued.After 48 hours, GC analysis indicated >98% conversion toortho-isopropoxy beta-methyl styrene. GC results: ortho-hydroxybeta-methyl styrene R^(t) 8.51 minutes and R^(t) 11.13 minutes (Z and Eisomers), ortho-isopropoxy beta-methyl styrene R^(t) 7.35 minutes(Z-isomer) and R^(t) 8.30 minutes (E-isomer).

The reaction was cooled to room temperature and 200 mL of water and 100mL of tertiary-butyl methyl ether (TBME) were added and mixed. Thephases were separated and the aqueous phase was washed with another 100ml of TBME. The organic phases were combined and washed with 2×100 mL ofwater, dried with anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to yield crude ortho-isopropoxy beta-methylstyrene. Vacuum distillation (Bpt_(1.0) 60° C. to 65° C.) yielded 61.3 g(348 mmol) or 93% isolated yield.

¹H NMR (300 MHz) CDCl₃ δ: 7.8 (d, 1H aromatic), 7.5 (m, 1H, aromatic),6.90 (bt, 2H, aromatic), 6.4 (dd, 1H, Ph—CH═CH), 6.0 (m, 1H,Ph—CH═CHCH₃), 4.64 (m, 1H, CH(CH₃)₂), 1.35 (6.3 Hz, 6H, CH(CH₃)₂). ³CNMR (75 MHz) CDCl₃ δ: 130.23, 127.68, 127.52, 126.36, 125.99, 125.71,125.53, 120.59, 119.92, 114.08, 113.96, 70.58, 22.298, 19.09, 14.87.

Example 3

Alternative Synthesis of ortho-Isopropoxy beta-Methyl Styrene 121:Synthesis of ortho-Isopropoxy Salicylaldehyde [3]. Similar to theprocecure of Example 2, 6.5 g (53.2 mmol) of salicylaldehyde, 100 mL ofanhydrous DMF, 6.5 g of K₂CO₃, and 10 g of isopropyl bromide (81.3 mmol)were added to a dry 250 nL round-bottom flask containing a magneticstirbar. The heterogeneous mixture was stirred with heating to 60° C.for 24 hours when GC analysis indicated complete conversion too-isopropoxy salicylaldehyde. Water 100 mL was added and the organicswere washed with 2×100 mL of TBME, the TBME phases were combined andwashed with 2×50 mL water, dried with anhydrous sodium sulfate, filteredand concentrated to yield [3] (8.3 g, 95% yield). Salicylaldehyde R^(t)6.473 minutes, ortho-isopropoxy salicylaldehyde R^(t) 10.648 minutes. ¹HNMR (300 MHz) CDCl₃ δ: 10.46 (CHO), 7.8 (d, 1H aromatic), 7.5 (m, 1H,aromatic), 6.90 (t, 2H, aromatic), 4.64 (m, 1H, CH(CH₃)₂, 1.35 (J 6.3Hz, 6H, CH(CH₃)₂.

Example 4

Alternative Synthesis of ortho-Isopropoxy beta-Methyl Styrene [2]:Synthesis of ortho-Isopropoxy(2′-Hydroxypropyl) Benzene [4]. To a 50 mLround-bottom flask was added 1 g (7.0 mmol) of [3] and 25 mL ofanhydrous tetrahydrofuran (THF). The flask was sparged with Argon whilecooling to −15° C. over 15 minutes. Ethyl magnesium chloride (3 mL of 3M in ether) was added drop wise over 10 minutes. The reaction was warmedto room temperature and quenched with water-saturated ammonium chloride.GC analysis indicated >99% conversion toortho-isopropoxy(2′-hydroxypropyl) benzene with R^(t)=10.969 minutes(4.1%) and 11.374 minutes (95.9%), E and Z isomers. The product wasisolated by usual methods to yield [4] (1.4 g, quantitative yield). Thisproduct was used in the next reaction without further purification.

Example 5

Alternative Synthesis of ortho-Isopropoxy beta-Methyl Styrene [2]. To a250 mL round-bottom flask was added 1.4 g (7.0 mmol) of [4], 100 mL ofanhydrous toluene, and 100 mg of p-toluene sulfonic acid. The mixturewas heated to 90° C. for 90 minutes when GC analysis indicated completeconversion to [2] with an isomeric ratio of E:Z isomers of 97:3. ¹H NMRand ¹³C NMR were in agreement with previously synthesized material.

Example 6

Synthesis of [(sIMES)(o-isopropoxyphenylmethylene)Ruthenium Dichloride][6] from (sIMES)(PCy₃)Cl₂Ru═CHPh [5] and CUCl. To a dry 100 mLround-bottom flask containing a magnetic stirbar, under argon, was added1.79 g (2.1 mmol, 1.0 equiv) [5], CuCl (521 mg, 5.28 mmol, 2.51 equiv),and 25 mL of anhydrous CH₂Cl₂. Ligand precursor [2] (403 mg, 2.1 mmol,1.0 equiv) was added to the reddish solution in 20 mL of CH₂Cl₂ at roomtemperature. A reflux condenser was added and the mixture was heated for70 minutes, under argon. The crude product was concentrated and loadedonto silica gel and eluted with 2:1 pentane:CH₂Cl₂ then 1:1pentane:CH₂Cl₂ to remove a dark green band. The column was washed withCH₂Cl₂, then Et₂O. The green and yellow bands were combined andconcentrated under reduced pressure to yield a dark green solid. Thesolvents are removed under reduced pressure and the solid wascrystallized from hexane to yield 1.07 g (1.70 mmol, 85%) of [6]. ¹H NMR(300 MHz, CDCl₃) δ: 16.56 (s, 1H, Ru═CHAr), 7.48 (m, 1H, aromatic CH),7.07 (s, 4H, mesityl aromatic CH), 6.93 (dd, J=7.4 Hz, 1.6 Hz, 1H,aromatic CH), 6.85 (dd, J=7.4 Hz, 1H, aromatic CH), 6.79 (d, J=8.6 Hz,1H, aromatic CH) 4.90 (septet, J=6.3 Hz, 1H,(CH₃)₂CHOAr), 4.18 (s, 4H,N(CH₂)₂N), 2.48 (s, 12H, mesityl o-CH₃), 2.40 (s, 6H, mesityl p-CH₃),1.27 (d, J=5.9 Hz, 6H, (CH₃)₂CHOAr. ¹³C NMR (75 MHz, CDCl₃) δ: 296.8 (q,J=61.5 Hz), 211.1, 152.0, 145.1, 145.09, 138.61, 129.4 (d, ^(J)NC 3.9Hz), 129.3, 129.2, 122.6, 122.1, 122.8, 74.9 (d, ^(J)OC 10.7 Hz), 51.4,30.9, 25.9, 21.01.

Example 7

Synthesis of [6] from (51 and Bleach. To a dry 100 mL round-bottom flaskcontaining a magnetic stirbar was added 1.79 g (2.1 mmol, 1.0 equiv) of[5], 10 mL of household bleach (i.e., aqueous sodium hypochlorite), and25 mL of CH₂Cl₂. Ligand precursor [21 (403 mg, 2.1 mmol, 1.0 equiv) wasadded to the reddish solution in 20 mL of CH₂Cl₂ at room temperature. Areflux condenser was added and the mixture was heated for 4 hours. Theorganic phase was washed with water, isolated, neutralized, dried,filtered and concentrated under reduced pressure to yield a green solid.Crystallization from pentane yielded 43% of [6] of acceptable purity asindicated by NMR spectral analysis.

Example 8

Synthesis of [6] from [5] and Ethereal HCl. To a dry 100 mL round-bottomflask containing a magnetic stirbar was added 1.79 g (2.1 nmol, 1.0equiv) of [5], 25 mL of CH₂Cl₂, and 2.4 mL of ethereal HCl (2.0 M, 2.0equiv). Ligand precursor [2] (420 mg, 2.4 mmol, 1.14 equiv) was added tothe reddish solution in 20 μL of CH₂Cl₂ at room temperature. A refluxcondenser was added and the mixture was heated for 1 hour. The organicphase was washed with 2×25 mL water, dried with anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to yield agreen solid. Crystallization from CH₂Cl₂/hexane yielded [6] (1.03 g, 78%yield) as indicated by NMR spectral analysis.

Example 9

Synthesis of [(PCy₃)(o-isoproxyphenylmethylene) Ruthenium Dichloride][8] from (PCy₃)₂Cl₂Ru═CHPh [7]. Ruthenium complex [7] (270 g, 0.32moles) was charged into a 2 L 3-neck roundbottom flask. Ligand precursor[2] (505 g, 2.8 moles) was then added, and one neck of the flask wasfitted with a gas adapter, another with a stopper and the third with adistillation head and receiver flask. The flask was placed under vacuumand slowly heated to 80° C. The mixture was maintained at between 65° C.and 70° C. under vacuum for 24 hours. The temperature was raised to 80°C. and the remaining ligand precursor was distilled away. The vacuum wasbroken and hexanes (1 L) was added to the flask. The reaction mixturewas stirred for several minutes then filtered. The solids were washedwith warm hexanes (3×100 mL) yielding [8] (96.2 g, 49% yield) asindicated by NMR spectral analysis.

Example 10

Synthesis of [8] from (PCy³)₂Cl₂Ru═CH—Cl₂H═C(CH₃)₂ [9]. Rutheniumcomplex (48 g, 0.059 moles) was charged to a 1 L roundbottom flask andligand precursor [2] was charged along with toluene (400 g). A refluxcondenser was attached to the flask and kept at 15° C. The mixture waswarmed to 70° C. under vacuum for 12 hours. The condensor was warmed to45° C. and the toluene was removed in vacuuo. The mixture was thenheated to 80° C. for 48 hours under a static vacuum. A distillation headwas attached to the flask and the remaining ligand precursor distilledaway in vacuo. 500 mL of hexanes was added to the flask and the mixturewas allowed to cool to room temperature with mixing. The mixture wasfiltered and the solids washed with hexanes (100 mL) yielding 16.7 g(46% yield) of [8] as indicated by NMR spectral analysis.

Example 11

Synthesis of [8] from [9] with Hydrochloric Acid. A mixture of methylenechloride (200 g) and ligand precursor [2] (200 g, 1.136 moles) wascharged into a roundbottom flask, warmed to 40° C., and degassed bysparging with nitrogen gas. Ruthenium complex [9] (100 g, 0.125 moles)was then added to the mixture against a nitrogen sparge. Hydrochloricacid (6N, 20 mL, 0.120 moles) was added slowly dropwise through anaddition funnel over a period of three hours to the stirred mixture,which was maintained at 40° C. under nitrogen. After stirring for anadditional hour at 40° C., analysis by thin-layer chromatography (TLC)indicated only partial conversion. The mixture was then stirred for anadditional two hours at 50° C. and 1 hour at 60° C. until TLC suggestednearly complete conversion. An additional 5 mL of 6N hydrochloric acidwas then added and the mixture stirred for two hours to assurecompletion. While still warm, 100 mL of methanol was added, and theresulting mixture poured into 1,400 mL of methanol to precipitate theproduct. The mixture was filtered and the solids washed and dried toyield 47.5 g (63% yield) of [8] as indicated by TLC analysis.

Example 12

Synthesis of [8] from [9] with Water. A mixture of toluene (200 mL),ligand precursor [2] (100 g, 0.568 moles), ruthenium complex [9] (49 g,0.061 moles) and water (100 mL) was charged into a roundbottom flask,sparged with nitrogen, and vigorously stirred overnight at 80° C.Analysis by TLC indicated nearly complete conversion. Hydrochloric acid(6N, 10 mL) was then added and the mixture stirred for several minutesto assure completion. The aqueous layer was removed and 400 mL ofmethanol added to precipitate the product. After stirring overnight, themixture was filtered and the solids washed with methanol (50 mL),acetone (50 mL) and hexanes (50 mL) and dried to yield 19 g (52% yield)of [8].

Example 13

Synthesis of [6] from [5] and Hydrochloric Acid in THF. Ligand precursor[2] (5.28 g, 0.030 mole) and 50 mL of a mixture of 1 part concentratedhydrochloric acid in 5 parts tetrahydrofuran were added to a dry 500 mLround-bottom flask containing a magnetic stirbar. The mixture wasdegassed for ten minutes with a nitrogen sparge before 10 g (0.012 mole)of [5] was added. The reaction mixture was then heated to 60° C. for twohours when TLC analysis indicated that conversion was complete. Aftercooling to room temperature, the product precipitated, was collected byfiltration, and washed with methanol to yield 4.33 g of [6] (59% yield).The filtrates were combined and refiltered to yield a second crop of1.07 g of [6], giving an overall yield of 73%.

Example 14

Synthesis of [6] from [5] and Hydrochloric Acid in THF. Ligand precursor[2] (2.64 g, 0.015 mole) and 30 mL of a mixture of 1 part concentratedhydrochloric acid in 5 parts tetrahydrofuran were added to a dryround-bottom flask containing a magnetic stirbar. The mixture wasdegassed for ten minutes with a nitrogen sparge before 10 g (0.012 mole)of [5] was added. The reaction mixture was then heated to 60° C. for twohours when TLC analysis indicated that conversion was complete. Aftercooling to room temperature, 30 mL of distilled water was added to helpprecipitate the product, which was collected by filtration and washedwith methanol to yield 5.37 g of [6] (73% yield).

Example 15

Synthesis of [6] from [5] and Gaseous Hydrogen Chloride. Ligandprecursor 12] (84 g, 0.477 mole), [5] (161 g, 0.190 mole), and 1.6 L ofmethylene chloride were added to a dry round-bottom flask containing amagnetic stirbar and degassed with a nitrogen sparge. Dry hydrogenchloride gas was then bubbled through the mixture for approximately tenseconds. After stirring for two hours, hydrogen chloride gas was againbubbled through the mixture for approximately ten seconds. After a totalof five hours of stirring, TLC analysis indicates complete conversion.The reaction mixture was concentrated by rotary evaporation before 500mL of methanol was added to precipitate the product, which was isolatedby filtration and washed twice with 100 mL of methanol to yield 97.5 g(82%) of [6].

Example 16

One-Pot Synthesis of [8] from Dichloro(1,5-cyclooctadiene)rutheniumDichloro(1,5-cyclooctadiene)ruthenium (4.0 g, 0.014 moles),tricyclohexylphosphine (8.4 g, 0.030 moles), degassed triethylamine (2mL), and degassed sec-butanol (60 ml) were combined in a pressure bottleunder argon. The pressure bottle was purged with hydrogen gas,pressurized to 60 psi, and the mixture heated to 80° C. for 18 hours(the bottle was repressurized as needed to maintain 60 psi hydrogen).The reaction mixture was then allowed to cool down and the hydrogen gaswas vented off. Degassed methanol (60 mL) was added to the orange slurryand the filtrate decanted off via stick filtration under argon to leavean orange solid in the bottle, which was washed with degassed methanol(60 mL). Degassed toluene (60 mL) was added to the orange solid and theorange slurry cooled to 0° C. Degassed 3-chloro-3-methyl-1-butyne (1.7mL, 0.015 moles) was added dropwise via syringe at 0° C. The orangeslurry progressively turned to a maroon slurry, while gas bubbled away.The mixture was stirred at room temperature for 2 hours after additionwas complete. Ligand precursor [2] (18 g, 0.102 moles) was then chargedand the mixture was heated to 80° C. and sparged with argon for 3 days(degassed toluene was added as needed). The brown slurry was allowed tocool to room temperature and a mixture of 30 mL methanol and 10 mL ofconcentrated hydrochloric acid was added in air with mixing. Afterstirring for 15 minutes at room temperature, the two phases were allowedto separate and the methanol phase was decanted off. Trituration withmethanol (2×50 mL) gave a solid, which was collected on a frit andwashed with more methanol (2×20 mL). The brown solid was then washedwith hexanes (2×20 mL) and dried to rive [8] (5.1 g, 0.085 moles) in 61%yield.

1. A method of preparing a metathesis-active metal carbene complex witha chelating carbene ligand comprising contacting the metathesis-activemetal carbene complex with an internal olefin ligand precursor of theformula:

wherein R³ and R⁴ are each, independently, selected from hydrogen or asubstitutent selected from the group consisting of alkyl, aryl, alkoxy,aryloxy, C₂–C₂₀ alkoxycarbonyl, and C₁–C₂₀ trialkylsilyl, wherein eachof the substituents is substituted or unsubstituted; R⁵, R⁶, R⁷, and R⁸are each, independently, selected from the group consisting of hydrogen,halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkenyloxy,aryloxy, alkoxycarbonyl, carbonyl, alkylamino, alkylthio; alkylsulfonyl,nitrile, nitro, alkylsulfinyl, trihaloalkyl, perfluoroalkyl, carboxylicacid, ketone, aldehyde, nitrate, cyano, isocyanate, hydroxyl, ester,ether, amine, imine, amide, sulfide, disulfide, sulfonate, carbamate,silane, siloxane, phosphine, phosphate, or borate; Y is a heteroatomselected from the group oxygen (O), sulfur (S), nitrogen (N), orphosphorus (P); n is 1, in the case of a divalent heteroatom such as Oor S, or 2, in the case of a trivalent heteroatom such as N or P; and Zis a group selected from hydrogen, alkyl, aryl, functionalized alkyl,functionalized aryl where the functional group(s) may independantly beone or more or the following: alkoxy, aryloxy, halogen, carboxylic acid,ketone, aldehyde, nitrate, cyano, isocyanate, hydroxyl, ester, ether,amine, imine, amide, sulfide, disulfide, carbamate, silane, siloxane,phosphine, phosphate, or borate.
 2. The method of claim 1 wherein Y isoxygen or sulfur; n is 1; Z is selected from the group consisting ofalkyl, aryl and trialkylsilyl; and R³ and R⁴ are both hydrogen.
 3. Themethod of claim 1 wherein Y is oxygen; n is 1; Z is selected from thegroup consisting of methyl, isopropyl, sec-butyl, t-butyl, neopentyl,benzyl, phenyl and trimethylsilyl; and R³, R⁴, R⁵, R⁶, R⁷, and R⁸ areeach hydrogen.
 4. The method of claim 1 wherein the ligand precursor isselected from the group consisting of 2-methoxy-β-methylstyrene,2-isopropoxy-β-methylstyrene and 2 -isopropoxy-3-phenyl-β-methylstyrene.5. The method of claim 1 wherein the method occurs in the presence of asolvent, and wherein the solvent is selected from the group consistingof chlorinated solvent, ethereal solvent, aromatic solvent, hydrocarbonsolvent and excess ligand precursor.
 6. The method of claim 1 furthercomprising adding a sequestering agent.
 7. The method of claim 6 whereinthe sequestering agent is CuCl.
 8. The method of claim 6 wherein thesequestering agent is selected from the group consisting of mineralacid, organic acid, and mild oxidant.
 9. The method of claim 6 furthercomprising crystallizing the product in the presence of an organicsolvent.
 10. A method of preparing a ruthenium complex with a chelatingcarbene ligand comprising contacting a ruthenium carbene complex of theformula X¹X² L¹L²M=CR¹R² with an internal olefin ligand precursor of theformula:

wherein X¹ and X² are each, independently, any anionic ligand; L¹ and L²are each, independently, any neutral electron donor, M is ruthenium; R¹and R² are each, independently, selected from hydrogen or a substitutentselected from the group consisting of alkyl, alkenyl, alkynyl, aryl,alkylcarboxylate, arylcarboxylate, alkoxy, alkenyloxy, alkynyloxy,aryloxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylsulfinyl, andtrialkylsilyl; wherein each of the substituents is substituted orunsubstituted; and wherein R¹ and R² may be linked to form a cyclicgroup; R³ and R⁴ are each, independently, selected from hydrogen or asubstitutent selected from the group consisting of alkyl, aryl, alkoxy,aryloxy, C₂–C₂₀ alkoxycarbonyl, and C₁–C₂₀ trialkylsilyl, wherein eachof the substituents is substituted or unsubstituted; R⁵, R⁶, R⁷, and R⁸are each, independently, selected from the group consisting of hydrogen,halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkenyloxy,aryloxy, alkoxycarbonyl, carbonyl, alkylamino, alkylthio, alkylsulfonyl,nitrile, nitro, alkylsulfinyl, trihaloalkyl, perfluoroalkyl, carboxylicacid, ketone, aldehyde, nitrate, cyano, isocyanate, hydroxyl, ester,ether, amine, imine, amide, sulfide, disulfide, sulfonate, carbamate,silane, siloxane, phosphine, phosphate, or borate; Y is a heteroatomselected from the group oxygen (O), sulfur (S), nitrogen (N), orphosphorus (P); n is 1, in the case of a divalent heteroatom such as Oor S, or 2, in the case of a trivalent heteroatom such as N or P; and Zis a group selected from hydrogen, alkyl, aryl, functionalized alkyl,functionalized aryl where the functional group(s) may independantly beone or more or the following: alkoxy, aryloxy, halogen, carboxylic acid,ketone, aldehyde, nitrate, cyano, isocyanate, hydroxyl, ester, ether,amine, imine, amide, sulfide, disulfide, carbamate, silane, siloxane,phosphine, phosphate, or borate.
 11. The method of claim 10 wherein atleast one of L¹ and L² is an N-heterocyclic carbene; Y is oxygen orsulfur; n is 1; Z is selected from the group consisting of alkyl, aryland trialkylsilyl; and R³ and R⁴ are both hydrogen.
 12. The method ofclaim 10 further comprising adding a sequestering agent selected fromthe group consisting of mineral acid, organic acid, and mild oxidant.13. The method of claim 10 wherein any two or more of X¹, X², and L¹ arelinked to form a multidentate ligand.
 14. The method of claim 10 whereinthe L¹ and L² ligands are linked to form a bidentate ligand.
 15. Amethod of preparing a ruthenium complex with a chelating carbene ligandcomprising contacting a ruthenium carbene complex of the formulaX¹X²L¹L²M=CR¹R² with an internal olefin ligand precursor of the formula:

wherein X¹ and X² are each Cl; L¹ is an N-heterocyclic carbene; L² isany neutral electron donor; M is ruthenium; R¹ and R² are each,independently, selected from hydrogen or a substitutent selected fromthe group consisting of alkyl, alkenyl, alkynyl, aryl, alkylcarboxylate,arylcarboxylate, alkoxy, alkenyloxy, alkynyloxy, aryloxy,alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylsulfinyl, andtrialkylsilyl; wherein each of the substituents is substituted orunsubstituted; and wherein R¹ and R² may be linked to form a cyclicgroup; R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are each hydrogen; Y is oxygen orsulfur; n is 1; and Z is a group selected from hydrogen, methyl,isopropyl, sec-butyl, t-butyl, neopentyl, benzyl, phenyl ortrimethylsilyl.
 16. The method of claim 15 further comprising adding asequestering agent selected from the group consisting of mineral acid,organic acid, and mild oxidant.
 17. The method of claim 16 furthercomprising crystallizing the product in the presence of an organicsolvent.